EP3402482A1 - Aleglitazar for the treatment of diabetic kidney disease - Google Patents

Aleglitazar for the treatment of diabetic kidney disease

Info

Publication number
EP3402482A1
EP3402482A1 EP16795042.7A EP16795042A EP3402482A1 EP 3402482 A1 EP3402482 A1 EP 3402482A1 EP 16795042 A EP16795042 A EP 16795042A EP 3402482 A1 EP3402482 A1 EP 3402482A1
Authority
EP
European Patent Office
Prior art keywords
aleglitazar
use according
axis
gfr
stabilization
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16795042.7A
Other languages
German (de)
French (fr)
Inventor
Regina DUTTLINGER MADDUX
Carl Anders SVENSSON
Jin Tian
Harold V. BARRON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP3402482A1 publication Critical patent/EP3402482A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to aleglitazar for use in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.
  • Aleglitazar is (S)-2-methoxy-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzo[b]thiophen-7-yl ⁇ -propionic acid. It belongs to the class of Peroxisome Proliferator Activated Receptors (PPAR) agonists. Aleglitazar is described in WO 02/092084.
  • Peroxisome Proliferator Activated Receptors are members of the nuclear hormone receptor super family, which are ligand- activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPAR alpha, PPAR beta (also known as PPAR delta) and PPAR gamma. There exist at least two major isoforms of PPAR gamma. While PPAR gamma 1 is ubiquitously expressed in most tissues, the longer isoform PPAR gamma2 is almost exclusively found in adipocytes. In contrast, PPAR alpha is predominantly expressed in the liver, kidney and heart. PPARs modulate a variety of body responses including glucose- and lipid- homeostasis, cell differentiation, inflammatory responses and cardiovascular events.
  • Aleglitazar is a potent, balanced dual PPAR alpha/gamma agonist. It combines the PPAR alpha with the PPAR gamma agonist effects.
  • AleCardio was a randomized, double-blind, placebo controlled, multicenter study to evaluate the effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome (ACS) in patients with type 2 diabetes mellitus.
  • the study design has previously been published in Lincoff et al., JAMA 2014 and Lincoff et al., Am Heart J.
  • DSMB DSMB
  • 7,226 patients who were hospitalized for ACS with either established or newly diagnosed type 2 diabetes were recruited between February 2010 and May 2012 from 722 centers in 26 countries.
  • the study was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated.
  • the trial was terminated in July 2013 following the DSMB's recommendation and 704 primary end points events (74% of those projected) had been positively adjudicated by December 17, 2013.
  • the study enrolled patients with type 2 diabetes mellitus and acute coronary syndrome (ACS) requiring hospitalization.
  • ACS acute coronary syndrome
  • Acute coronary syndrome included myocardial infarction, with or without ST segment elevation on the electrocardiogram or biomarker- negative unstable angina.
  • Exclusion criteria included symptomatic heart failure, hospitalization with heart failure within the previous 12 months, severe peripheral edema, estimated glomerular filtration rate of ⁇ 45 mL/min/1.73 m or fasting triglyceride level greater than 400 mg/dL.
  • Patients could be randomized at hospital discharge following the qualifying ACS event or after a screening period of no longer than 12 weeks to allow stabilization of their clinical condition, completion of planned revascularization procedures and achievement of steady-state renal function.
  • Patients were assigned in a double-blind fashion under a 1 : 1 ratio using a permuted block randomization without stratification through an interactive telephone and web system to receive aleglitazar 150 ⁇ g daily or matching placebo, in addition to
  • the patients who had a linear GFR decline were selected for the analysis of the renal effect (UACR is Urine Albumin to Creatinine Ratio).
  • the baseline mean blood pressure (BP) was 141/79 mmHg and 140/79 mmHg respectively for aleglitazar and placebo group and the mean BP level was stable during the treatment phase until the end of follow up.
  • BP Urine Albumin to Creatinine Ratio
  • the mean eGFR slope the rate of yearly GFR loss or the rate of yearly kidney function decline
  • the rate of kidney function loss was significantly slower in the aleglitazar group than that in the placebo group.
  • the kidney function was then stabilized in the aleglitazar group whereas it continued to decrase in the placebo group.
  • Figure 1 represents the eGFR slope analysis for patients with baseline eGFR inferior to 80 mL/min/1.73 m and UACR superior to 300 mg/mg.
  • Placebo (N 144) 143 135 130 122 118 115 88 58 30 5
  • the rate of kidney function decline was over 4 mL/min/year in the placebo group (receiving standard of care).
  • the initial drop of GFR in the aleglitazar group was due to hemodynamic response, which is reversible after stopping the drug.
  • the invention thus relates to aleglitazar for use in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.
  • Patients having a linear decline in GFR are patients having a progressive decline in renal function.
  • a linear decline in GFR is characterized by a negative slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis).
  • the invention further relates to alelgitazar for use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria.
  • the invention further relates to aleglitazar for use as defined above wherein macroalbumineria is characterized by a UACR superior to 300 mg/g.
  • the invention thus relates to aleglitazar for use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and a UACR superior to 300 mg/g.
  • the invention also relates to aleglitazar for use as defined above wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease.
  • End stage kidney disease occurs when the kidneys are no longer able to support the body's needs and work at a level needed for a day-to-day life.
  • the invention further relates to:
  • Aleglitazar for use as defined above, wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss; Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis);
  • Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar;
  • Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 6 months of treatment with aleglitazar;
  • Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 18 months of treatment with aleglitazar;
  • the invention further relates to:
  • aleglitazar for the manufacture of a medicament for treating or preventing diabetic kidney disease, wherein the diabetic kidney disease is caused by a linear decline in GFR;
  • macroalbumineria is characterized by a UACR superior to 300 mg/g;
  • treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease;
  • the medicament comprises a dose of aleglitazar of 150 ug
  • a method for treating or preventing diabetic kidney disease in a patient in need thereof and having a linear decline in GFR comprising the administration of aleglitazar to the patient;
  • macroalbumineria is characterized by a UACR superior to 300 mg/g;
  • the method as defined above wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease;
  • the method as defined above wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss;
  • the method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis);
  • the method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar;
  • kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 6 months of treatment with aleglitazar;
  • the method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 18 months of treatment with aleglitazar;

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of aleglitazar in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.

Description

Aleglitazar for the treatment of diabetic kidney disease
The present invention relates to aleglitazar for use in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.
Aleglitazar is (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzo[b]thiophen-7-yl}-propionic acid. It belongs to the class of Peroxisome Proliferator Activated Receptors (PPAR) agonists. Aleglitazar is described in WO 02/092084.
Peroxisome Proliferator Activated Receptors (PPAR) are members of the nuclear hormone receptor super family, which are ligand- activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPAR alpha, PPAR beta (also known as PPAR delta) and PPAR gamma. There exist at least two major isoforms of PPAR gamma. While PPAR gamma 1 is ubiquitously expressed in most tissues, the longer isoform PPAR gamma2 is almost exclusively found in adipocytes. In contrast, PPAR alpha is predominantly expressed in the liver, kidney and heart. PPARs modulate a variety of body responses including glucose- and lipid- homeostasis, cell differentiation, inflammatory responses and cardiovascular events.
Aleglitazar is a potent, balanced dual PPAR alpha/gamma agonist. It combines the PPAR alpha with the PPAR gamma agonist effects.
In the randomized clinical trial AleCardio (Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus), although aleglitazar reduced hemoglobin AIC and improved serum HDL-C and triglyceride levels, consistently with other previous PPAR studies, it did not significantly decrease the incidence of cardiovascular death, myocardial infarction or stroke in the overall population. Additionally, aleglitazar treatment showed increased risks of heart failure, renal dysfunction, bone fracture, GI bleeding and hypoglycemia. However, aleglitazar surprisingly demonstrated in this study a positive effect on the stabilization of renal function in patients who had a linear decrease in GFR (glomular filtration rate).
AleCardio was a randomized, double-blind, placebo controlled, multicenter study to evaluate the effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome (ACS) in patients with type 2 diabetes mellitus. The study design has previously been published in Lincoff et al., JAMA 2014 and Lincoff et al., Am Heart J.
2013;166(3):429-434. The study protocol was approved by the institutional review board of each center and all patients gave written informed consent. The study was overseen by steering and safety committees. The steering committee oversaw the study design, the study conduction and the study data analysis. A Data and Safety Monitoring Board
(DSMB), consisting of independent physicians and statisticians with access to unblinded data, monitored the safety of the study. 7,226 patients who were hospitalized for ACS with either established or newly diagnosed type 2 diabetes were recruited between February 2010 and May 2012 from 722 centers in 26 countries. The study was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. However, the trial was terminated in July 2013 following the DSMB's recommendation and 704 primary end points events (74% of those projected) had been positively adjudicated by December 17, 2013. The study enrolled patients with type 2 diabetes mellitus and acute coronary syndrome (ACS) requiring hospitalization. Acute coronary syndrome included myocardial infarction, with or without ST segment elevation on the electrocardiogram or biomarker- negative unstable angina. Exclusion criteria included symptomatic heart failure, hospitalization with heart failure within the previous 12 months, severe peripheral edema, estimated glomerular filtration rate of <45 mL/min/1.73 m or fasting triglyceride level greater than 400 mg/dL. Patients could be randomized at hospital discharge following the qualifying ACS event or after a screening period of no longer than 12 weeks to allow stabilization of their clinical condition, completion of planned revascularization procedures and achievement of steady-state renal function. Patients were assigned in a double-blind fashion under a 1 : 1 ratio using a permuted block randomization without stratification through an interactive telephone and web system to receive aleglitazar 150 μg daily or matching placebo, in addition to
contemporary and guideline-based care for ACS, diabetes, and coronary heart disease risk factors (baseline characteristics of the treatment is described in JAMA 2014 cited above). Concomitant use of systemic corticosteroids for longer than 2 weeks, thiazolidinediones or fibrates was not permitted. Patients returned for outpatient visits at 1, 3, 6, 9 and 12 months following randomization, followed by alternating visits and phone contact every third month thereafter. The study drug was not interrupted until the repeated test of serum creatinine value was superior to 50% increase over the baseline visit.
In order to evaluate the renal function decline, the patients who had a linear GFR decline (defined as estimated GFR<80 ml/min/1.73 m and UACR>300 mg/g) were selected for the analysis of the renal effect (UACR is Urine Albumin to Creatinine Ratio). The baseline mean blood pressure (BP) was 141/79 mmHg and 140/79 mmHg respectively for aleglitazar and placebo group and the mean BP level was stable during the treatment phase until the end of follow up. Surprisinlgy, after initial drop of eGFR (estimated glomular filtration rate), the mean eGFR slope (the rate of yearly GFR loss or the rate of yearly kidney function decline) in the chronic phase was stabilized over the next 18 months. The rate of kidney function loss was significantly slower in the aleglitazar group than that in the placebo group. The kidney function was then stabilized in the aleglitazar group whereas it continued to decrase in the placebo group.
This is represented in Figure 1. Figure 1 represents the eGFR slope analysis for patients with baseline eGFR inferior to 80 mL/min/1.73 m and UACR superior to 300 mg/mg.
The patient number under each data point of the GFR slope of Figure 1 is given in Table 1.
Table 1
Month
Treatment group Baseline 1 3 6 9 12 18 24 30 36
Placebo (N=144) 143 135 130 122 118 115 88 58 30 5
Aleglitazar (N=154) 153 139 131 118 102 90 74 47 19 4
The patient number decreased significantly after month 24 due to the early termination of the AleCardio study, therefore only the results until month 24 can be considered.
In the subgroup of patients who have linear GFR decline (eGFR<80mL/min/1.73 m and UACR>300 mg/g), after initial drop of the eGFR, the rate of GFR loss in the aleglitazar treated group (79% on angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB)) was halted to a stable level; but the placebo group (79% on ACEi or ARB) continued to have progressive GFR drop. This is the first GFR slope analysis that shows the stabilization of renal function from a randomized placebo controlled trial in diabetic nephropathy patients.
The rate of kidney function decline (GFR loss) was over 4 mL/min/year in the placebo group (receiving standard of care). The rate of kidney function decline became flat in the chronic phase in the aleglitazar group (receiving aleglitazar on top of standard of care).
The initial drop of GFR in the aleglitazar group was due to hemodynamic response, which is reversible after stopping the drug.
The invention thus relates to aleglitazar for use in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.
Patients having a linear decline in GFR are patients having a progressive decline in renal function.
A linear decline in GFR is characterized by a negative slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis). The invention further relates to alelgitazar for use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria.
The invention further relates to aleglitazar for use as defined above wherein macroalbumineria is characterized by a UACR superior to 300 mg/g.
The invention thus relates to aleglitazar for use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and a UACR superior to 300 mg/g.
The invention also relates to aleglitazar for use as defined above wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease.
End stage kidney disease occurs when the kidneys are no longer able to support the body's needs and work at a level needed for a day-to-day life.
The invention further relates to:
Aleglitazar for use as defined above, wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss; Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis);
Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar;
Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 6 months of treatment with aleglitazar;
Aleglitazar for use as defined above wherein the stabilization of kidney function is characterized by a positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 18 months of treatment with aleglitazar;
Aleglitazar for use as defined above wherein aleglitazar is for oral use; Aleglitazar for use as defined above wherein aleglitazar is for use once a day; Aleglitazar for use as defined above wherein aleglitazar is for use at a dose of 150
Aleglitazar for use as defined above wherein aleglitazar is for oral use at a dose of
150 ug once a day.
The invention further relates to:
The use of aleglitazar in the manufacture of a medicament for treating or preventing diabetic kidney disease in a patient having a linear decline in GFR; The use of aleglitazar in the manufacture of a medicament for treating or preventing diabetic kidney disease in a patient, wherein the diabetic kidney disease is characterized by a linear decline in GFR;
The use of aleglitazar for the manufacture of a medicament for treating or preventing diabetic kidney disease, wherein the diabetic kidney disease is caused by a linear decline in GFR; The use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria;
The use as defined above wherein macroalbumineria is characterized by a UACR superior to 300 mg/g;
The use as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and a UACR superior to 300 mg/g;
The use as defined above wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease;
The use as defined above wherein the stabilization of kidney function is
characterized by the halt of progressive kidney function loss;
The use as defined above wherein the stabilization of kidney function is
characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis);
The use as defined above wherein the stabilization of kidney function is
characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar;
The use as defined above wherein the stabilization of kidney function is
characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 6 months of treatment with aleglitazar;
The use as defined above wherein the stabilization of kidney function is
characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 18 months of treatment with aleglitazar;
The use as defined above wherein the medicament comprises a dose of aleglitazar of 150 ug;
The use as defined above wherein the medicament is for oral administration;
The use as defined above wherein the medicament is for administration once a day; The use as defined above wherein the medicament is for oral administration at a dose of 150 ug once a day;
A method for treating or preventing diabetic kidney disease in a patient in need thereof and having a linear decline in GFR comprising the administration of aleglitazar to the patient;
The method as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria;
The method as defined above wherein macroalbumineria is characterized by a UACR superior to 300 mg/g; The method as defined above wherein the patient has a GFR inferior to 80 mL/min/1.73 m and a UACR superior to 300 mg/g;
The method as defined above wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease; The method as defined above wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss;
The method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis); The method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar;
The method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 6 months of treatment with aleglitazar;
The method as defined above wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 18 months of treatment with aleglitazar; The method as defined above wherein aleglitazar is administered at a dose of 150 ug;
The method as defined above wherein aleglitazar is oraly administered;
The method as defined above wherein aleglitazar is administered once a day; and
The method as defined above wherein aleglitazar is oraly administered once a day at a dose of 150 ug.

Claims

Claims
1. Aleglitazar for use in the treatment or prevention of diabetic kidney disease in a patient having a linear decline in GFR.
2. Alelgitazar for use according to claim 1, wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria.
3. Aleglitazar for use according to claim 2, wherein macroalbumineria is characterized by a UACR superior to 300 mg/g.
4. Aleglitazar for use according to any one of claims 1 to 3, wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease.
5. Aleglitazar for use according to claim 4, wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss.
6. Aleglitazar for use according to claim 4 or 5, wherein the stabilization of kidney function is characterized by a positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis).
7. Aleglitazar for use according to any one of claims 4 to 6, wherein the stabilization of kidney function is characterized by a positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar.
8. Aleglitazar for use according to any one of claims 1 to 7, wherein aleglitazar is for oral use at a dose of 150 ug once a day.
9. Use of aleglitazar in the manufacture of a medicament for treating or preventing diabetic kidney disease in a patient having a linear decline in GFR.
10. Use according to claim 9, wherein the patient has a GFR inferior to 80 mL/min/1.73 m and macroalbumineria.
11. Use according to claim 10, wherein macroalbumineria is characterized by a UACR superior to 300 mg/g.
12. Use according to any one of claims 9 to 11, wherein the treatment or prevention of diabetic kidney disease comprises the stabilization of kidney function and the prevention of end stage kidney disease.
13. Use according to claim 12, wherein the stabilization of kidney function is characterized by the halt of progressive kidney function loss.
14. Use according to claim 12 or 13, wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis).
15. Use according to any one of claims 12 to 14, wherein the stabilization of kidney function is characterized by a null or positive slope of the curve plotting the absolute change in estimated GFR compared to baseline (Y axis) against time (X axis) after 3 months of treatment with aleglitazar.
16. Use according to any one of claims 9 to 15, wherein the medicament comprises a dose of of aleglitazar of 150 ug.
17. Use according to any one of claims 9 to 16, wherein the medicament is for oral administration.
18. Use according to any one of claims 9 to 17, wherein the medicament is for
administration once a day.
19. The invention as herein before described.
***
EP16795042.7A 2015-11-18 2016-11-14 Aleglitazar for the treatment of diabetic kidney disease Withdrawn EP3402482A1 (en)

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Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
ME01310B (en) 2001-05-15 2011-10-10 Hoffmann La Roche Carboxylic acid substituted oxazole derivatives for use as ppar-alpha and -gamma activators in the treatment of diabetes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A. B?NARDEAU ET AL: "Effects of the dual PPAR-[alpha]/[gamma] agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat", DIABETES, OBESITY AND METABOLISM, vol. 15, no. 2, 3 October 2012 (2012-10-03), pages 164 - 174, XP055168875, ISSN: 1462-8902, DOI: 10.1111/dom.12006 *
BALAKUMAR P ET AL: "Emerging role of PPAR ligands in the management of diabetic nephropathy", PHARMACOLOGICAL RESEARCH, ACADEMIC PRESS, LONDON, GB, vol. 60, no. 3, 1 September 2009 (2009-09-01), pages 170 - 173, XP026391575, ISSN: 1043-6618, [retrieved on 20090131] *
See also references of WO2017084989A1 *

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